Staphylococcus aureus continues to be a major human pathogen causing skin and deep soft-tissue infections that may complicate implanted devices and surgical wound sites. The increasing prevalence of staphylococcal strains that are resistant to antibiotics looms as a threat to patients and the public health. Novel preventive and therapeutic approaches are needed for combating this pathogen. Since adherence of staphylococci to host tissues is critical for colonization and infection, staphylococcal surface proteins are likely to be the first point of contact between the bacterium and the host and, thus, are important preventive targets. Of the staphylococcal surface proteins that bind to host structures, the fibronectin-binding proteins (FnBP) are the major fibronectin (Fn)-binding adhesions and mediate bacterial adherence and intracellular invasion in vitro. A recent study has confirmed the importance of FnBP in the initiation of infection in an endocarditis model. Unfortunately, most attempts to use FnBP as a vaccine target have been hampered by poor blocking capacity of anti-FnBP antibodies. In a non-vaccine approach, a fragment of the FnBP of S. aureus has been used to prevent the establishment of wound infection in a guinea pig model. One explanation of this mode of action of FnBP is that it competitively blocks the binding of staphylococci to host targets such as Fn and/or other receptors. The preventive effects of this FnBP fragment In wound infection prophylaxis are likely broadly applicable to most S. aureus strains given that the capacity to bind Fn is common for almost all staphylococcal strains. Observations from prior studies of the FnBP molecule using recombinant and synthetic FnBP constructs will be applied to the wound infection model in an effort to identify critical regions within FnBP that are responsible for the preventive effect in this animal model. Also, anti-adhesive and/or inflammatory mechanisms that may be operative in the preventive effect of FnBP will be examined. The use of FnBP as an anti-adhesin presents a novel therapeutic tool for the prevention of S. aureus infections.